Elucidating the physiological function of alpha-synuclein is important because mutations in this protein are implicated as a causative factor in familial Parkinson disease (PD) and because alpha-synuclein is associated with a number of other neurodegenerative diseases. Preliminary data contained herein indicates that alpha-synuclein dramatically affects steady-state lipid mass in brain and in isolated synaptosomes, suggesting that alpha-synuclein has a significant impact on brain phospholipid metabolism. Collectively, these changes, along with others, could alter the basal biophysical state of the membrane as well as decrease intracellular second messenger generation via a reduction in lipid-mediated signaling. Thus, it is critical to address the mechanism(s) by which alpha-synuclein affects brain lipid metabolism to gain a greater understanding regarding the potential physiological role for alpha-synuclein in the brain. The following specific aims are designed to address the impact that alpha-synuclein has on brain phospholipid metabolism using a combination of whole animal, cell culture, and in vitro approaches. Aim 1. Determine the effect alpha-synuclein on brain phospholipid metabolism in vivo using steady-state radiotracer kinetics to assess the kinetics phospholipid biosynthesis and downstream processing in alpha-synuclein gene-abated and control mice. Aim 2. Determine the effect of alpha-synuclein on cellular phospholipid metabolism ex vivo using stable isotopes and radiotracers to assess the kinetics of phospholipid biosynthesis and downstream processing in neurons and glia isolated from alpha-synuclein gene-abated and control mice. Aim 3. Compare the effects of mutant and wild-type alpha-synuclein on phospholipid metabolism in stably transfected HEK-293 cells using stable isotopes and radiotracers to assess the kinetics of phospholipid biosynthesis and downstream processing. Aim 4. Determine the ability of wild-type and mutant alpha-synuclein to directly alter phospholipid biosynthesis in vitro using a combination of approaches. These aims are designed to address the following hypothesis: alpha-Synuclein stimulate phospholipid synthesis through a direct stimulation of phosphatidic acid biosynthesis, thereby increasing the phosphatidic acid pool available for use in downstream synthesis of specific phospholipids.